Is CLEC16A p.Val652Met (c.1954G>A) pathogenic?

CLEC16A p.Val652Met (c.1954G>A) is classified Uncertain significance in CLEC16A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-17). AlphaMissense: likely benign (0.3381); Ultra-rare (popmax 0.0493%, mid).

How common is CLEC16A p.Val652Met (c.1954G>A) in the general population?

CLEC16A p.Val652Met (c.1954G>A) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about CLEC16A p.Val652Met (c.1954G>A)?

AlphaMissense predicts likely benign (score 0.3381) — an in-silico prediction, not a clinical call.

CLEC16A p.Val652Met

c.1954G>A · rs200827060 · VCV2294352

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3381 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3381	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 199 kb · p 0.087 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00508% 82/1,613,896 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
South Asian	0.0242%	4,141
Remaining individualsnot grpmax-eligible	0.0176%	5,678
European (non-Finnish)	0.00381%	26,220
Admixed American	0.00167%	60,012

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CLEC16A
Protein: p.Val652Met
Coding: c.1954G>A
MANE Select: NM_015226
dbSNP: rs200827060
Type: single nucleotide variant
Location: chr16:11051600 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.17

Full CLEC16A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC16A p.Glu432= Benign/Likely benign ★★ same type
CLEC16A p.His31= Likely benign ★★ same type
CLEC16A p.Leu948Phe Benign ★★ same type
CLEC16A p.Ser892Asn Likely benign ★★ same type
CLEC16A p.Ser982Asn Likely benign ★★ same type
CLEC16A p.Thr475Met Benign/Likely benign ★★ same type
CLEC16A p.Ala1043Val Uncertain significance ★ ⚠ same type
CLEC16A p.Ala347Thr Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/clec16a-p-val652met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown